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Inhibition of SIRT7 Overcomes Radioresistance in Pancreatic Neuroendocrine Tumors by Reactivating MEN1 Expression
Jianyun Jiang1,2, Yan Wang1,2,3,4,5, Yi Qin1,2,3,4,5
1Center For Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China.
Abstract:
Pancreatic neuroendocrine tumors (PanNETs) frequently exhibit loss or reduced expression of the tumor suppressor MEN1, a key regulator of tumor progression and DNA damage response (DDR). However, the upstream mechanisms driving MEN1 silencing remain unclear. Here, a pooled epigenetic CRISPR-Cas9 screen identified the NAD+-dependent deacetylase SIRT7 as a critical suppressor of MEN1 expression. Mechanistically, SIRT7 interacts with DNMT1 and promotes catalytic activity-dependent recruitment of DNMT1 to the MEN1 promoter, leading to promoter hypermethylation and transcriptional repression. Clinically, SIRT7 is overexpressed in PanNET tissues and inversely correlates with MEN1 levels and patient prognosis. Genetic or pharmacologic inhibition of SIRT7 restored MEN1 expression, reduced MRN complex abundance, and impaired double-strand break repair. Graded MEN1 re-expression demonstrated a quantitative relationship between MRN levels, DNA repair efficiency, and radiosensitivity. Functionally, SIRT7 inhibition enhanced radiation-induced DNA damage and apoptosis in a partially MEN1-dependent manner and significantly suppressed tumor growth in patient-derived organoids and multiple independent xenograft models. Collectively, these findings define a catalytic activity-dependent SIRT7-DNMT1-MEN1 epigenetic axis that modulates DDR and radiosensitivity, supporting SIRT7 targeting as a strategy to improve radiotherapy efficacy in PanNETs.
Insights
Scientists discovered SIRT7 silences the MEN1 tumor suppressor in pancreatic neuroendocrine tumors (PanNETs) by promoting DNA methylation. Inhibiting SIRT7 restores MEN1, enhances DNA repair, and improves radiosensitivity, offering a new therapeutic strategy for PanNETs.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Pancreatic neuroendocrine tumors (PanNETs) often show reduced expression of the MEN1 tumor suppressor.
- The mechanisms causing MEN1 silencing in PanNETs are not fully understood.
Purpose of the Study:
- To identify upstream regulators of MEN1 expression in PanNETs.
- To investigate the role of SIRT7 in MEN1 regulation and its therapeutic potential in PanNETs.
Main Methods:
- Pooled epigenetic CRISPR-Cas9 screening to identify regulators of MEN1.
- Mechanistic studies involving SIRT7, DNMT1, and MEN1 promoter methylation.
- Analysis of SIRT7 and MEN1 expression in PanNET tissues.
- In vitro and in vivo experiments evaluating SIRT7 inhibition effects on DNA damage response, radiosensitivity, and tumor growth.
Main Results:
- SIRT7 was identified as a key suppressor of MEN1 expression via catalytic activity-dependent recruitment of DNMT1 to the MEN1 promoter, causing hypermethylation.
- SIRT7 is overexpressed in PanNETs, inversely correlating with MEN1 levels and poorer patient prognosis.
- SIRT7 inhibition restored MEN1 expression, impaired DNA double-strand break repair, and enhanced radiosensitivity.
- Targeting SIRT7 suppressed tumor growth in patient-derived organoids and xenograft models.
Conclusions:
- A novel epigenetic axis (SIRT7-DNMT1-MEN1) regulating DNA damage response and radiosensitivity in PanNETs was defined.
- SIRT7 inhibition represents a promising strategy to enhance radiotherapy efficacy for PanNET patients.
